The ICH M7 guideline1 presents the types of methodologies that are relevant to assess mutagenic impurities. The guideline goes further than simply mentioning that QSAR methods and analogs should be considered prior to conducting an experimental study, and it details two complementary methodologies (statistical and expert rule-based), and how the results should be considered to derive an assessment of mutagenicity. These principles could be used in the safety assessment of extractables and leachables to assess mutagenicity, if warranted. However, there are additional areas of toxicology which may be relevant for the safety assessment of extractables and leachables which could benefit from such procedural descriptions such as skin sensitization, and dermal and ocular irritation.  Databases and tools are in place for utilizing existing information to make reliable predictions of a leachable’s toxicity.

The procedures described in the ICH M7 guideline1 for mutagenicity allow the assessor to obtain accurate and consistent predictions while reaping practical benefits. A harmonized guideline which details the strategic use of in silico methods for safety assessments will reduce the burden on assessors and regulators to perform or review an in silico toxicological assessment. Given our experience conducting assessments, here are some aspects of best practice considerations for in silico assessments.

  • An important step is assessing the adequacy and reliability of data in the public domain, including conflict resolutions. This may circumvent the need for in silico testing.
  • Two complementary methodologies (statistical and expert rule-based) offer an advantage. While statistical based methodologies assess all areas of the molecule and the structural basis for the prediction can be explained, the alerts identify reactive groups that are linked to a mechanism. However, it can be difficult to support negative predictions using alerts alone. Rules should be defined to derive a consensus based on the two methodologies which generate conservative predictions.
  • Criteria illustrated with case-studies should be defined for an expert review, such as, how to assess a chemical which shares an alert with a known negative.

There is much anticipation for the ICH Q3E2 guideline in the assessment of extractables and leachables.

Please get in touch if you would like to have a copy of a recent poster that was presented at ACT on this topic (


 1. ICH. M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals  to limit potential carcinogenic risk (R1). 2017.

2. Final Concept Paper ICH Q3E: Guideline for Extractables and Leachables (E&L). 2020.